Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT02853292 |
| Other study ID # |
PO16055 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
May 2016 |
| Est. completion date |
May 2022 |
Study information
| Verified date |
June 2022 |
| Source |
CHU de Reims |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
Intravenous high-dose amoxicillin is a frequently prescribed antibiotic in intensive care
units and infectious disease departments, in such indications as meningitis, endocarditis,
listeriosis, or documented susceptible osteo-articular infections.
Among possible side effects is the occurrence of amoxicillin crystalluria. Its incidence is
unknown. It is deemed uncommon but literature is poor and its incidence is probably
under-estimated. It can be complicated with hematuria or acute renal failure and may require
renal replacement therapy. measures that can limit the impact of this nephrology
crystalluria.
Since the beginning of 2014, because of the occurrence of a case of macroscopic crystalluria
in our unit and a pharmacovigilance alert, it has been decided to search systematically for
amoxicillin crystalluria in several centers of the north-east of France. The investigators
propose to study these patients, through an observational study of a multicenter longitudinal
cohort, to assess the incidence of amoxicillin crystalluria during high dose intravenous
amoxicillin treatment.
Description:
Amoxicillin is an antibiotic of the family of β-lactams and sub-family penicillin A. It has a
time-dependent bactericidal activity. It is mainly active on many bacterial species
frequently found in infectious diseases. It can be administered orally or parenterally. It is
therefore a frequently prescribed antibiotic, alone or in combination. Its elimination is
mainly urinary in its active form. It is frequently prescribed intravenously at high doses in
infectious disease departments, in indications like meningitis, endocarditis, listeriosis, or
documented susceptible osteo-articular infections.
Several amoxicillin treatment side effects have been reported, like hypersensitivity
reactions, gastrointestinal adverse reactions, mucocutaneous candidiasis, nervous system
toxicity and eventually kidney disease, namely the occurrence of crystalluria or acute
interstitial nephritis of whose frequency is undetermined.
Literature concerning the occurrence of crystalluria is mainly based on Case reports and
there are no incidence data. Crystalluria is characterized by the presence of amoxicillin
trihydrate crystals in urine, after amoxicillin urinary supersaturation. The appearance is
that of large needles, isolated or aggregated into "broom bush-like" crystal, 50-300µm, with
birefringent under polarized light. Amoxicillin crystalluria may be of varying importance,
microscopic or macroscopic, sometimes up to urinary tract obstruction and may cause acute
renal failure (ARF) and require renal replacement therapy. A low urine output could be
associated with the occurrence of crystalluria, as well as a urine pH between 5 and 7, a high
urinary density and high doses of amoxicillin.
Amoxicillin crystalluria is deemed uncommon. In the national pharmacovigilance database, in
November 2013, there were only 9 reported cases, from 12 to 78 years old, 5 of whom severe
one of which life-threatening. There is a high underreporting in these data, and it seems
that this impact is highly underestimated for several reasons: amoxicillin crystalluria is
not sought in routine clinical practice in all centers, even with high dose administrated. It
is not clinically detectable if microscopic and even if a urine culture is performed,
amoxicillin crystals may be mistaken for other crystals. In the investigator's experience
automated systems do not always detect these crystals. Moreover, patients likely to receive
high doses of amoxicillin are generally subject to severe infections and are more at risk of
acute renal failure either due to background or previously initiated therapies (like the
association with aminoglycosides), and the imputability of a crystalluria in the occurrence
of an episode of acute renal failure among these patients is seldom considered.
Finally, a recent increase in the number of reported cases in the national pharmacovigilance
database is an incentive to pay more attention to this complication.
The investigators also think that the occurrence of an amoxicillin crystalluria, even apart
from extreme cases of macroscopic crystalluria complicated by oligo-anuric ARF, could
increase the risk of intra-hospital ARF. The demonstration of such an effect associated with
an incidence of significant crystalluria might justify the research in routine practice among
patients receiving intravenous high-dose amoxicillin (IHDA).
The search for amoxicillin crystalluria is rather simple, by performing a direct microscopic
examination of the urine. If in doubt about the diagnosis amoxicillin composition of these
crystals, due to an atypical appearance or concomitant administration of other drugs that may
generate similar crystals, the sample may be sent to a specialized laboratory for infrared
spectroscopy to confirm that it is amoxicillin crystals.
IHDA treatments would be the situations with a higher risk for crystalluria. The highlighting
of such an effect associated to a significant incidence of crystalluria might justify
systematic research recommendations in routine practice with patients receiving IHDA.
Following the occurrence in the infectious disease department of the Reims university
hospital of a case of macroscopic crystalluria complicated by ARF requiring renal replacement
and a pharmacovigilance alert, the search for amoxicillin crystalluria has been systematic as
well as in several centers of the Grand East of France with patients receiving IHDA to have
the possibility to watch these patients carefully at kidney level.
The investigators propose, through an observational study of a multicenter longitudinal
cohort, to assess the incidence of amoxicillin crystalluria during IHDA, to search for the
factors associated with the occurrence of this crystalluria and measure the impact of this
crystalluria on the occurrence of an episode of intra-hospital ARF.
Data will be collected in patients' paper or computerized record at the Center.
- Sociodemographic data.
- Weight and size
- Medical history
- Date of beginning and end of hospitalization, date of beginning and end of antibiotic
therapy
- Ongoing treatments / Absorption of nephrotoxics or diuretics / Associated antibiotics
- Indication of amoxicillin treatment
- intravenous intake and urine output
- Amoxicillin dosage and amoxicillin brand used and administration route
- Biological data
- Amoxicillin crystalluria (Quantification) / Presence of other crystals
- Amoxicillin dosage (if performed)
- urine dipstick
- urine sediment and bacteriological analyses
- Urinary pH
- Creatinine and creatinine clearance according to the MDRD formula (on entrance,
when starting treatment, on departure, minimum and maximum).
- Albuminemia
- Characteristics of a possible episode of acute renal failure occurring within 28 days
following IHDA
- Retained mechanism of acute renal failure
- Renal ultrasound results (if performed).
- Search for crystalluria
Statistical aspects:
1. Justification of the number of subjects needed The impact of drug related crystalluria
during amoxicillin treatment is unknown. Literature on this subject is composed of case
reports. However a frequency lower than 5% during IHDA would not be of significant
clinical interest. The number of subjects needed was then calculated with a 5% alpha
risk, an expected frequency of 10% with an accuracy of 5%, leading to a required number
of subjects of 139 patients. Taking into account 10% of possible exclusions, we plan to
include 153 patients.
According to the observed incidence of crystalluria, an extension of the number of
subjects needed will be discussed secondarily by investigators to obtain the necessary
power to assess the impact of crystalluria on the risk of acute renal failure.
2. Statistical analysis :
1. Flowchart :
The synthesis of the patients included, excluded and analyzed will be expressed in
the form of a flowchart.
2. Analysis of the primary endpoint:
It is a descriptive analysis of the cumulative incidence of amoxicillin crystalluria under
IHDA. It will be expressed as a percentage and its 95% confidence interval.
c. Secondary endpoints : i. Descriptive analysis : Quantitative variables of normal
distribution are described by their mean and standard deviation, and quantitative variables
of non-normal distribution are described by their median and interquartile range. Qualitative
variables are described by their frequency and percentages.
ii. Univariate analysis : Depending on the secondary endpoint, the variable to be explained
(dependent variable) is the occurrence of crystalluria or the occurrence of acute renal
failure. The measure of associations will be made by calculating odds ratios and their 95%
confidence intervals.
iii. Multivariate analysis : Depending on the number of events, multivariate analysis with a
binary logistic regression model will be proposed.
On the factors favoring the occurrence of crystalluria, the variables are those with a
p-value less than 0.20 in univariate analysis. Amoxicillinemia will be forced into the model.
On the factors favoring the occurrence of acute renal failure, the variables are those with a
p-value less than 0.20 in univariate analysis. The occurrence of crystalluria will be forced
into the model.
The associations measurements will be made by calculating adjusted odds ratio and their 95%
confidence interval.
